1. Field of the Invention
The present invention relates to novel compounds which are .beta.-lactamase inhibitors, pharmaceutical compositions containing the same and methods of inhibiting .beta.-lactamases. More specifically this invention is concerned with novel 7-alkylidene cephalosporins and pharmaceutically acceptable salts thereof.
2. Description of the Background
The most important mechanism of microbial resistance to .beta.-lactam antibiotics is the bacterial production of .beta.-lactamases, enzymes which hydrolytically destroy .beta.-lactam antibiotics, such as penicillins and cephalosporins. This type of resistance can be transferred horizontally by plasmids that are capable of rapidly spreading the resistance, not only to other members of the same strain, but even to other species. Due to such rapid gene transfer, a patient can become infected with different organisms, each possessing the same .beta.-lactamase.
.beta.-lactamase enzymes have been organized into four molecular classes: A, B, C, and D based on amino acid sequence. Class A, which includes RTEM and the .beta.-lactamase of Staphylococcus aureus, class C, which includes the lactamase derived from P99 Enterobacter cloacae, and class D are serine hydrolases. Class A enzymes have a molecular weight of about 29 kDa and preferentially hydrolyze penicillins. The class B lactamases are metalloenzymes and have a broader substrate profile than the proteins in the other classes. Class C enzymes include the chromosomal cephalosporinases of gram-negative bacteria and have molecular weights of approximately 39 kDa. The recently recognized class D enzymes exhibit a unique substrate profile which differs significantly from both class A and class C.
The class C cephalosporinases, in particular, are responsible for the resistance of gram-negative bacteria to a variety of both traditional and newly designed antibiotics. The Enterobacter species, which possess a class C enzyme, are now the third greatest cause of hospital-acquired infections in the United States. This class of enzymes often has poor affinities for inhibitors of the class A enzymes, such as clavulanic acid, a commonly prescribed inhibitor, and to common in vitro inactivators, such as 6-.beta.-iodopenicillanate.
One strategy for overcoming rapidly evolving bacterial resistance is the synthesis and administration of .beta.-lactamase inhibitors. Frequently, .beta.-lactamase inhibitors do not possess antibiotic activity themselves and are thus administered together with an antibiotic. One example of such a synergistic mixture is "augmentin which is a registered trademark of the Smithkline Beechom Corporation", which contains the antibiotic amoxicillin and the .beta.-lactamase inhibitor, clavulanic acid.
It is thus desirable to find novel .beta.-lactamase inhibitors which can be coadministered with a .beta.-lactam antibiotic.